Drug delivery device for buccal and aural applications and other areas of the body difficult to access

ABSTRACT

A device for delivering a drug includes a delivery tube wherein the delivery tube has a pressure chamber therein and at least one nozzle at a distal end of the delivery tube and in fluid communication with the pressure chamber. A source of drug is adjacent the at least one nozzle and a handle is located at a proximal end of the delivery tube. An energy source is located in the handle for providing a driving pressure of up to about 2,000 psi within the delivery tube for driving the drug through the at least one nozzle and out of the delivery tube. The delivery device is particularly useful for delivering drug under microjet propulsion to the mouth, ear and other areas of the body that are difficult to access.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates, in general, to drug delivery and, inparticular, to a new and useful device and method for the needle-freedelivery of drugs with minimal trauma to tissue and that are suitablefor delivering drugs in sensitive areas of the body such as the eye,nasal passageways, mouth and other areas of the body.

Despite the continual advances in medical technology, particularly inthe treatment of various diseases such as heart disease, vasculardisease, ophthalmic disease, cancer, pain, allergies, orthopedic repairand many other diseases and conditions, there are a significant numberof patients for whom conventional surgical and interventional therapiesare not feasible or are insufficient to treat the disease or condition.For many patients, medical treatment with drugs and the like is the onlyfeasible treatment available.

There have been many recent advances in drug therapies, particularlywith regard to cell or site-specific therapeutics also known as “local”drug delivery. Unlike the systemic administration of therapeutics,typically taken orally or given intravenously, much of the effectivenessof local drug delivery or cell or site-specific therapeutics is based onthe ability to accurately and precisely deliver the therapeutics to thetargeted site within the body.

Needle injection devices are the most commonly used means for the localdelivery or site-specific administration of agents or solutions.Although there have been advances in needle-based drugdelivery/injection systems, these systems have significant shortcomingsand disadvantages. One such disadvantage is that the use of a needle orother penetrating means to inject the targeted tissue area unavoidablyinvolves making a hole into the target site thereby causing trauma andtissue injury at the local tissue site.

Another disadvantage with this needle penetrating and injection approachis that it is very common for a substantial amount of the injectate toleak back out or exude from the hole created by the needle orpenetrating member. Often, this leaked injectate is releasedsystemically throughout the body or is wasted depriving the patient ofthe prescribed therapy or dosing amounts of the drug. This also resultsin increased treatment costs and requires more injections, time andagent in order to achieve the desired affect.

Furthermore, it is known that needle injections or penetration into thetissue can traumatize or destroy tissue cells and, as a result, increasea patient's risk of post-operative trauma, pain and discomfort at thelocal site and surrounding area. This is particularly due to thedifficulty in precisely controlling the penetration of the needle duringinjection. The more injections or penetrations, the greater the celldestruction and tissue trauma that is likely experienced. Still anotherdisadvantage of needle-based injections, especially where multipleinjections are required, is the inability to carefully track thelocation of each injection site so as to prevent the accidental deliveryof drug to non-diseased tissue or repeat delivery of the drug to thesame injection hole.

Other known drug delivery devices and methods do not involveneedle-based drug delivery. Instead, devices such as indwellingcatheters are used for releasing the therapeutic agent in a steady,controlled-release fashion. These types of devices could present agreater risk of releasing the agent systemically. Additionally, withthese types of devices, it is more difficult to assess the actual dosingof the target area that takes place. Thus, these types of devices havethe disadvantages of being less effective, possibly not as safe, anddefinitely more costly than the commonly known needle injectionapproaches and technology.

Another condition in which site-specific or local drug delivery iscommonly employed is in the treatment of peripheral vascular disease(such as deep vein thrombosis and embolisms). One such treatment isvenous lytic therapy, the dissolving of blood clots (thrombus) in theperipheral vasculature (e.g., femoral and iliac arteries and veins).Lytic therapy involves systemically infusing thrombolytics, such asurokinase, streptokinase, reteplase and tPA. Other more recentlydeveloped procedures involve directly delivering the thrombolytics intothe thrombus site through the use of indwelling infusion catheters. Inorder to effectively lyse the thrombus, the thrombolytics are typicallyinfused for many hours, even as much as a day or more, increasing thenecessary length of hospital stay and the overall cost of the procedure.

One common approach for eliminating a needle in local drug delivery isto use conventional needle-free jet injectors. Needle-free jet injectiontechnology was introduced nearly 40 years ago for use in massimmunization campaigns. Today, more than fifteen companies develop andmanufacture jet injectors for the intradermal and transdermal(subcutaneous and intramuscular) delivery of drugs. And while thesemodern designs offer tremendous improvements in size, cost andconvenience over their predecessors, the fundamental functionality hasremained unchanged. Principally, compressed gas is used to drive amedicament (either liquid or dry powder) through a single orifice atmoderately high speed, allowing the medicament to be deposited in orbeneath the skin by piercing through it. One example of a knownneedle-free jet injector is disclosed in WO 00/35520 and U.S. Pat. No.6,406,455 B1 (Willis et al.—assigned to BioValve Technologies, Inc.).

Further, needle-free jet injection has long been touted as a painlessprocedure, but clinical studies comparing jet injecting devices to aconventional needle and syringe have shown pain scores to be equivalentto that of a 25 ga. needle. In great part, this is due to the size ofthe injection stream and, thus, the size of the nozzle orifice. Existingdevices all use a nozzle orifice of about 0.006″ to 0.008″ in diameter.These conventional needle-free jet injectors are known to incorporateonly a single injection chamber and inject the entire drug contentthrough a single plastic nozzle having a typical orifice diameter of0.006″-0.008″ or 150-200 microns (0.15 mm-0.2 mm). These jet injectorstypically deliver volumes ranging from 0.100 cc (100 micro liters) to0.500 cc (500 micro liters), and even as much as 1 cc (1,000 microliters). There are several significant limitations with current jetinjection technology. First, injection times associated with theseconventional needle-free jet injectors are typically several seconds inlength, which puts the patient at risk of laceration if they should move(e.g., flinch) or if the injector should be jarred from the injectionsite during an injection. Second, the perceived pain is equivalent to aconventional needle and syringe. This has perhaps been the greatestsingle reason why jet injection has not been more widely accepted.Third, jet injectors are prone to deliver so-called “wet injections”where medicine leaks back out through the site of injection, a resultthat has given rise to concerns about accuracy of the delivered dose.

The first two items, pain and wet injections, are the result of thenozzle orifice size (approximately 0.006″ in current jet injectors).This size resulted more from the practical limitations of plasticinjection molding for high volume commercial manufacturing than from anyeffort at optimizing the size for user comfort and minimization orelimination of any “leaking” of the injected medicament. This trade-offof sub-optimal performance for manufacturability has resulted in amarginalized product that has not enjoyed the market acceptance itotherwise might have.

One particular type of conventional needle free jet is described in U.S.Pat. No. 6,716,190 B1 (Glines et al.) which teaches a device and methodsfor the delivery and injection of therapeutic and diagnostic agents to atarget site within a body. This device and method uses a complex systemcomprising a nozzle assembly having an ampule body and channels milledor machined within the distal surface of the ampule body. These channelsoperate as a manifold and are arranged orthogonal to a reservoirorifice. The reservoir orifice ejects or expels the contents containedwithin the ampule body to the orthogonally arranged channels whichchannel the contents to a plurality of dispersion orifices orthogonallyarranged to the channels. The dispersion orifices are orthogonal to thechannels and located within the generally planar distal target-facingsurface. Not only is this particular arrangement complex, but itrequires high delivery pressures for the contents in the ampule in arange from about 1800 to 5000 psi, with some applications in a rangefrom about 1800 to 2300 psi. Additionally, the dispersion orifices havea diameter of from about 0.1 mm to about 0.3 mm (100 to 300 microns).Even though such a device does not use a needle, the negative outcomeinvolved with using such a device and arrangement is that it is likelyto cause excessive trauma to the tissue at the delivery site as well ascause unwanted and unnecessary pain and/or discomfort to the end user orpatient due to the required high delivery pressures as well as therelatively large size of the dispersion orifices. Accordingly, theGlines et al. device and method are not suitable for microjet deliveryof drugs especially in sensitive areas of the body such as the eye,nasal passageways and mouth or other sensitive areas of the bodyespecially those areas that are easily prone to trauma, pain anddiscomfort.

Accordingly, there are a number of sensitive areas in the body anddisease states that are extremely difficult to treat using local drugdelivery. For example, there are a myriad of ophthalmic diseases thatare difficult to treat and delivery of the drug to the site of disease,i.e. the eye, is often painful or psychologically uncomfortable for thepatient. Relevant examples of these diseases that are extremelydifficult to treat include age-related macular degeneration (AMD),diabetic retinopathy, choroidal neovascularization (CNV), macular edema,uveitis, and the like.

For these types of disease, systemic administration of drug commonlyyields subtherapeutic drug concentrations in the eye and may havesignificant adverse effects. Consequently, current treatment fordiseases of the eye often involves direct injection of the medicamentinto the eye via a conventional needle and syringe a painful andundesirable means of delivery for the patient. Further, chronictreatment requires repeated injections that can result in plaqueformations and scarring in the eye, retinal detachment, andendophthalmitis.

As a result of these complications, alternative means of drug deliveryto the eye are being developed. Research areas for delivery includeiontophoresis, drug-eluding ocular implants, photodynamic therapy,“sticky” eye drops, and the like. And, it is well established that eachof these approaches has its own limitations.

For instance, iontophoresis has a practical limit to the size of thedrug molecule being delivered. It could not, for instance, be expectedto deliver molecules with a molecular weight above 20,000 Daltons. Yet,many new compounds, especially some promising proteins, are well abovethis size, ranging to as large as 150,000 Daltons.

Additionally, ocular implants require a surgical procedure forimplantation and explantation—procedures that are costly, painful, andcan result in scarring to the eye. Implants have the further limitationof physical size and the amount of drug that can be loaded or put onboard the implant.

It is also known that photodynamic therapy is an unproven technologywhose long-term effects are not understood and may well be harmful tothe retina. Alternatively, eye drops have long been considered the mostconvenient (and therefore perceived to be more acceptable) means ofdelivery of drugs to the eye. Eye drops, however, are very quicklywashed out of the eye and afford only minimal delivery of the containeddrug.

As a result, “sticky” eye drops, that is eye drops which provide mucosaladhesion, have been developed to prevent the “wash-out” effect. But, therapidity of the cellular turnover at the surface of the eye is believedto be limiting in the effectiveness of this means of delivery. Further,the mechanism of delivery from eye drops is passive diffusion across thesclera. And, passive diffusion cannot deliver drugs with a molecularweight greater than about 500 Daltons. Still further, the delivery issystemic rather than targeted to the eye itself.

Consequently, there are currently no truly acceptable means ofdelivering active therapeutic agents to the eye and other sensitiveareas of the body, especially the emerging macromolecules that areshowing promise in the treatment of a variety of ophthalmic diseases anddiseases associated with these other sensitive areas of the body.

To date, there have been no known devices or methods that provide fortrue needle-free delivery of drugs regardless of size of the drugmolecules involved as well as provide for true needle-free delivery ofdrugs with minimal trauma to tissue and that are suitable for deliveringdrugs in sensitive areas of the body such as the eye, nasal passagewaysor mouth.

To date, there have also been no known devices that provide for the trueneedle-free delivery of drugs wherein the devices are microjet deliverydevices that are simple and efficient in design and construction, lowcost and easy to manufacture.

SUMMARY OF THE INVENTION

The present invention is directed to new and useful devices and methodsfor the needle-free delivery of drugs with minimal trauma to tissue andthat are suitable for delivering drugs in sensitive areas of the bodysuch as the eye, nasal passageways, mouth and other areas of the body.

Thus, the present invention is directed to a device for delivering adrug comprising:

-   -   a housing;    -   at least one nozzle at a portion of the housing;    -   a source of drug in the housing; an energy source for providing        a driving pressure of from about 800 to about 2,000 psi for        driving the drug through the at least one nozzle and out of the        housing.

Additionally, the drug is driven through the at least one nozzle withina time ranging from about 10 msec to about 200 msec upon activation ofthe energy source. Moreover, the at least one injection nozzle has adiameter ranging between about 10 μm to about 50 μm.

Furthermore, the present invention is also directed to a device fordelivering a drug comprising:

-   -   a delivery tube, the delivery tube having a pressure chamber        therein;    -   at least one nozzle at a distal end of the delivery tube and in        fluid communication with the pressure chamber;    -   a source of drug adjacent the at least one nozzle;    -   a handle at a proximal end of the delivery tube; and    -   an energy source in the handle for providing a driving pressure        from about 800 to about 2,000 psi for driving the drug through        the at least one nozzle and out of the delivery tube.

Additionally, the present invention is also directed to a method formaking a jet injection drug delivery device, wherein the drug deliverydevice has at least one drug reservoir and at least one injectionnozzle, wherein the method comprises the steps of:

-   -   identifying a drug desired to be delivered;    -   identifying a volume of the drug desired to be delivered;    -   establishing a reservoir diameter for the at least one drug        reservoir;    -   establishing a nozzle diameter for the at least one injection        nozzle;    -   identifying a tissue model for delivery of the drug;    -   identifying a penetration depth in the tissue model for the        delivery of the drug; and    -   injecting the drug into the tissue model under variable pressure        until the desired penetration depth is achieved.

Moreover, the method further comprises identifying an optimal pressurerange for the drug delivery device that achieves the desired penetrationdepth. An optimal pressure range for the device according to the presentinvention is from about 800 to about 2,000 psi and an optimal pressurerange at a tip of the at least one injection nozzle for the device ofthe present invention is from about 4,000 to about 25,000 psi.

The present invention is also directed to a method for delivering a druginto tissue comprising the steps of:

-   -   providing a drug delivery device having at least one nozzle and        a drug contained in a portion of the device;    -   identifying a site for delivery of the drug in or on tissue;    -   placing a portion of the device on or near the site; and    -   delivering the drug into the tissue at the site through at least        one nozzle of the device under microjet propulsion at a driving        pressure from about 800 to about 2,000 psi.

The method further comprises delivering the drug into the tissue at thesite with a pressure at a tip of the at least one nozzle ranging up toabout 4,000 to about 25,000 psi.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. The invention itself, however, both as toorganization and methods of operation, together with further objects andadvantages thereof, may be understood by reference to the followingdescription, taken in conjunction with the accompanying drawings inwhich:

FIG. 1 is a perspective view of one embodiment of a microjet drugdelivery device in accordance with the present invention;

FIG. 2 is an exploded view of the device of FIG. 1 in accordance withthe present invention;

FIG. 3 is a view in cross-section of the device of FIG. 1 in a pre-firedconfiguration in accordance with the present invention;

FIG. 4 is a view in cross-section of the device of FIG. 1 in a firedconfiguration in accordance with the present invention;

FIG. 5 is a proximal, perspective view of another embodiment of amicrojet drug delivery device particularly useful for applications suchas ocular use in accordance with the present invention;

FIG. 6 is distal, perspective view of the device of FIG. 5 in accordancewith the present invention;

FIG. 7A is a view in cross-section of the device of FIG. 5 in accordancewith the present invention;

FIG. 7B is a view in cross-section of an alternative embodiment of thedevice of FIG. 7A having an LED focusing light in accordance with thepresent invention;

FIG. 8 is side view in partial cross-section of another embodiment of amicrojet drug delivery device particularly useful for applications suchas nasal use in accordance with the present invention;

FIG. 9 is a partial, enlarged side view of the distal end of the deviceof FIG. 8 in accordance with the present invention;

FIG. 10 is an illustration of the device in FIG. 8 in use for a nasalapplication in accordance with the present invention; and

FIG. 11 is a graph depicting depth of penetration versus pressure studyfor the microjet drug delivery device having nozzle diameter of 50 μmand volume of drug delivered of 100 μl in accordance with the presentinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to novel drug delivery devices, theirmethods of manufacture and their methods of use. As best shown in FIGS.1-10, the present invention is a needle-free (needle-less) microjet drugdelivery device 20, 20 a and 20 b, their methods of manufacture andtheir methods of use which are all elaborated in greater detail below.The drug delivery device 20, 20 a and 20 b, in accordance with thepresent invention is a needle-free jet injection device that deliversdrugs, such as liquid drug formulations, to a patient by injecting veryfine streams of the drug formulations at high velocity. Drug deliverydevice 20, 20 a and 20 b provides for a less painful means ofadministering drugs than a conventional needle and syringe devices aswell as known needle-less injection devices. Drug delivery device 20, 20a and 20 b, in accordance with the present invention, can be used in avariety of medical applications, including transdermal, dermal,intra-ocular, intranasal, oral, and, generally, transmucosal drugdelivery.

The terms “drug delivery device”, “delivery device”, “needle-free drugdelivery device”, “needle-free microjet drug delivery device”, “microjetdrug delivery device”, “needle-less drug delivery device”, “needle-lessmicrojet drug delivery device”, “needle-free jet injection device”,“needle-less jet injection device”, “jet injection device”, “microjetdevice” and “microjet” including various combinations of any parts ofthese terms, are all intended to have the same meaning and are usedinterchangeably herein.

The terms “active agent formulation” and “drug formulation” and“formulation” intends the drug or active agent optionally in combinationwith pharmaceutically acceptable carriers and additional inertingredients. The formulation can be either in solid, liquid orsemi-solid or semi-liquid or combinations thereof.

The terms “drug”, “agent”, active agent” and “pharmaceuticalcomposition” are used interchangeably herein and refer to an agent,drug, compound, composition of matter or mixture thereof, including itsformulation, which provides some therapeutic, often beneficial, effect.This includes pesticides, herbicides, germicides, biocides, algicides,rodenticides, fungicides, insecticides, antioxidants, plant growthpromoters, plant growth inhibitors, preservatives, antipreservatives,disinfectants, sterilization agents, catalysts, chemical reactants,fermentation agents, foods, food supplements, nutrients, cosmetics,drugs, vitamins, sex sterilants, fertility inhibitors, fertilitypromoters, microorganism attenuators and other agents that benefit theenvironment of use. As used herein, the terms further include anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; avians; domestic household or farmanimals such as cats, dogs, sheep, goats, cattle, horses and pigs;laboratory animals such as mice, rats and guinea pigs; fish; reptiles;zoo and wild animals; and the like. The active drug that can bedelivered includes inorganic and organic compounds, including, withoutlimitation, drugs which act on the peripheral nerves, adrenergicreceptors, cholinergic receptors, the skeletal muscles, thecardiovascular system, smooth muscles, the blood circulatory system,synoptic sites, neuroeffector junctional sites, endocrine and hormonesystems, the immunological system, the reproductive system, the skeletalsystem, autacoid systems, the alimentary and excretory systems, thehistamine system and the central nervous system. Suitable agents may beselected from, for example, proteins, enzymes, hormones,polynucleotides, nucleoproteins, polysaccharides, glycoproteins,lipoproteins, polypeptides, steroids, hypnotics and sedatives, psychicenergizers, tranquilizers, anticonvulsants, muscle relaxants,antiparkinson agents, analgesics, anti-inflammatories, localanesthetics, muscle contractants, antimicrobials, antimalarials,hormonal agents including contraceptives, sympathomimetics, polypeptidesand proteins capable of eliciting physiological effects, diuretics,lipid regulating agents, antiandrogenic agents, antiparasitics,neoplastics, antineoplastics, hypoglycemics, nutritional agents andsupplements, growth supplements, fats, ophthalmics, antienteritisagents, electrolytes and diagnostic agents.

Examples of drugs or agents useful in this invention includeprochlorperazine edisylate, ferrous sulfate, aminocaproic acid,mecaxylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, methamphetamine hydrochloride, benzphetamine hydrochloride,isoproteronol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindione, diphenadione, erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-.beta.-estradiol, ethinylestradiol, ethinyl estradiol 3-methyl ether, prednisolone,17-.beta.-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, indomethacin, naproxen, fenoprofen,sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol,timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine,levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine,theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin,erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine,phenoxybenzamine, diltiazem, milrinone, captropril, mandol, quanbenz,hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen,tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine,nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine,tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril,captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate,etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam,amitriptylin, and imipramine. Further examples are proteins and peptideswhich include, but are not limited to, insulin, colchicine, glucagon,thyroid stimulating hormone, parathyroid and pituitary hormones,calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,follicle stimulating hormone, chorionic gonadotropin, gonadotropinreleasing hormone, bovine somatotropin, porcine somatropin, oxytocin,vasopressin, prolactin, somatostatin, lypressin, pancreozymin,luteinizing hormone, LHRH, interferons, interleukins, growth hormonessuch as human growth hormone, bovine growth hormone and porcine growthhormone, fertility inhibitors such as the prostaglandins, fertilitypromoters, growth factors, human pancreas hormone releasing factor,antiproliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP)II_(b)III_(a) inhibitors and vitronectin receptor antagonists;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);antiinflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetominophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF) platelet derived growth factor (PDGF), erythropoetin;angiotensin receptor blocker; nitric oxide donors; anti-senseoligionucleotides and combinations thereof; cell cycle inhibitors, mTORinhibitors, growth factor signal transduction kinase inhibitors,chemical compound, biological molecule, nucleic acids such as DNA andRNA, amino acids, peptide, protein or combinations thereof.

It is to be understood that more than one drug or agent may be combinedor mixed together and incorporated into or used by the presentinvention, and that the use of the term “drug”, “agent”” or “drug” or“pharmaceutical composition” in no way excludes the use of two or moresuch drugs, agents, active agents and or pharmaceutical compositions.

One embodiment of the drug delivery device 20 in accordance with thepresent invention is illustrated in FIGS. 1-4. The drug delivery device20 is a needle-free jet injection device especially useful for injectingdrug delivered under microjet propulsion in very fine streams at highvelocity into various types of body tissue, to include organs. By way ofexample, the drug delivery device 20 in accordance with the presentinvention is particularly useful for the dermal or transdermal deliveryof drugs to a patient, i.e. as a dermal or transdermal drug deliverydevice for delivering drugs without a needle to the various layers ofskin or through the layers of skin and into the patient's blood streamand circulatory system. Although, the drug delivery device 20, inaccordance with the present invention, is not limited to dermal andtransdermal applications, but rather, is intended to be used for othertypes of tissue and other medical, therapeutic and diagnosticapplications.

The drug delivery device 20 has a housing 24 and a cap 28 at a proximalend of the housing 24 and a nozzle plate 30 at the distal end of thehousing 24. One or more nozzles 34 or a plurality of nozzles 34, whichare jet injection nozzles (also referred to as “micronozzles”), arearranged in the nozzle plate 30. As shown in FIGS. 1-4, injectionnozzles 34 terminate as small outward protrusions from the outer surfaceof nozzle plate 30 thereby providing the user with tactile feedback forthe proper positioning and alignment of the injection nozzles 34 on thesurface of the user's body tissue. As best illustrated in FIGS. 2, 3 and4, housing 24 further includes one or more reservoirs 38 aligned withand in fluid communication with the one or more nozzles 34. Eachreservoir 38 is longitudinally arranged in the housing 24 and serves asa drug reservoir or storage space for drug 40.

Each reservoir is shaped to receive a pushrod 48 and a reservoir seal 54attached or fixed to the distal end of each pushrod 48. Pushrod 48 andreservoir seal 54 are in direct longitudinal alignment with eachreservoir 38 and pushrod 48 and reservoir seal are movably located(longitudinally movable) within each drug reservoir 38. Each reservoirseal 54 is designed to prevent drug 40 from leaching or leaking from thedrug reservoir 38. Thus, reservoir seal 54 is in movable sealablecontact with the inner wall of the drug reservoir 38.

The pushrod 48 and reservoir seal 54 are slidably movable longitudinallyin each reservoir 38. Piston 44 is integral to or fixed to the proximalend of each pushrod 48 and serves as a driving platform for accumulatingand exerting a driving force to the pushrods 48. Piston 44 can be fixedas a single unit to the proximal end of all pushrods 48 in order tooperate and move each pushrod 48 simultaneously within each reservoir 38or piston 44 can be fixed to the proximal end of each pushrod 48individually in order to selectively and individually operate and moveeach pushrod 48 within reservoir 38.

In this example, piston 44 has a cylindrical shape shaped to fitsecurely within and in moveable engagement with inner wall of housing 24that is also of a cylindrical shape. Piston 44 has a circumferentialspace shaped to receive an O-ring seal 52 that is also shaped to fitsecurely within and in moveable engagement with inner wall of housing 24along with piston 44. Seal 52 can be any type of seal so long as itprevents gas, discharge contents, or other matter from leaking orpenetrating past piston 44.

As best shown in FIG. 3 (drug delivery device 20 loaded with drug 40 andin its pre-fired configuration), an energy source for discharging adriving force to the piston 44 is located proximal or superior to thepiston 44 within housing 24, for instance, in one embodiment accordingto the present invention, a charge housing 60 located in the proximal orsuperior portion of the housing 24. Pyrotechnic charge 64 is containedwithin charge housing 60. A primer 68 is located adjacent pyrotechniccharge 64 for holding a small explosive charge that delivers pyrotechnicenergy or ignition energy to the pyrotechnic charge 64 for igniting thepyrotechnic charge 64 upon activation of primer 68.

A striker pin 70 is located in cap 28 and moveably engages or moveablycontacts primer 68 for activating primer 68 and initiating the explosivecharge contained in primer 68. Striker pin 70 is moveably connected toan activation element such as an activation button 74 that is movablybiased by spring 72. Thus, activation button is movably biased tostriker pin 70 within cap 28 for driving striker pin 70 into the primer70 upon a sufficient downward force pressed upon activation button 74,for instance, by the thumb of the user or patient.

As best shown in FIG. 4 (drug delivery device 20 in its firedconfiguration after having injected drug 40 under microjet propulsion),upon depressing the activation button 74, striker pin 70 strikes primer68 thereby activating primer 68, which, in turn, cause the extremelyrapid combustion of a pyrotechnic charge 64. This controlled explosionprovides the driving force necessary to slidably advance the piston 44and the affixed pushrods 48 through the reservoirs 48 causing thepushrods 48 to expel by microjet propulsion the drug 40 out through theinjection nozzles 34.

The energy source, such as pyrotechnic charge 64 or compressed gas 36(FIGS. 8 and 10) delivers sufficient energy and driving pressure to maindrive piston 44 and associated pushrods 48 that ranges from about 800 toabout 2,000 psi. In turn, the energy and pressure at the tips ofmicrozzles 34 ranges from about 4,000 to about 25,000 psi at eachmicrozzle tip, and preferably at a range from about 8,000 to about12,000 psi at each microzzle tip, and more preferably at about 10,000psi at each microzzle tip.

For all embodiments of the present invention, the same referencenumerals are used to designate the same or similar features and parts.Accordingly, FIGS. 5, 6, 7A and 7B, illustrate another embodiment of thepresent invention that is particularly useful for ophthalmic and ocularapplications such as delivering drug 40 a patient eye 100. Thus, nozzleplate 30 a at distal end of housing 24 has a contoured distal end 31that is a concave ring having an opening in a center portion thereof. Inthis example, contoured distal end 31 has a plurality of injectionnozzles 34 circumferentially arranged within the contour (concaveregion) defined by the contoured distal end 31 and spaced proximally adistance away from the outer surface edge of the outer circumference(periphery or outer edge) of contoured distal end 31. Accordingly, inthis example, nozzle plate 30 a having contoured distal end 31 is shapedto receive a patient's eye 100 wherein the pupil of the eye 100 can besituated within the center portion (open space) of the circumferentialring of the contoured distal end 31. Thus, if desired, drug 40 can bedelivered under microjet propulsion to areas of the eye 100 outside thepupil, such as the vitreous or sclera, as best shown in FIG. 5.

FIG. 7B depicts an alternative embodiment of drug delivery device 20 awherein a light emitting diode (LED) cavity 76 is provided at the centerportion (open space) of the circumferential ring of the contoured distalend 31 of nozzle plate 30 a. An LED 80 is positioned in the LED cavity76 for dispersing a focusing light (focusing LED light) 88 underoperational control from switch 86 movably positioned at an exteriorportion of the housing 24 (in this example near the proximal end ofhousing 24). Switch 86 serves as a power switch for activating LED 80 toproject focusing light 88, i.e. switch 86 serves as an “On”, “Off”switch for the LED 80 and light 88. For sake of brevity, the contacts,leads and wires operatively connecting the LED 80 to the switch 86 arenot shown, but are well understood and can be well appreciated by onehaving a level of ordinary skill in this field.

Focusing light 88 is used to attract the direct attention of thepatient, align and focus the pupil of eye 100 and serves as a focalpoint of patient's attention in order to get the patient to mentallyrelax (basically distract the patient) while drug 40 is delivered to theeye 100 under microjet propulsion. Thus, LED 80 and focusing light 88serves as a means for lowering the patient's stress levels and anxietynormally associated with receiving a drug injection, particularly, insuch a sensitive area as the eye 100.

Alternatively, in lieu of an LED 80, an element or feature that isluminescent (including self-luminescent) or an element or feature havinga luminescent coating, such as a dot having self-luminescent coatingthat is used as a focal point and can be used to attract the directattention of the patient and focus of the pupil of eye 100 for servingas a focal point of patient's attention in order to get the patient tomentally relax in anticipation of and while receiving the injected drug40 under microjet propulsion. A tritium-coated dot is one of thesesuitable substitutes as an example.

FIGS. 8, 9 and 10 illustrate another embodiment of the present inventionwherein the drug delivery device 20 b uses an elongated, cylindricaltube as a delivery tube 25 having a pressure chamber 27 therein. Ahandle 23 is connected to the delivery tube 25 at a proximal portion ofthe delivery tube 25. A valve 33 is connected to the proximal end of thedelivery tube 25 and pressure chamber 27 and a source of compressed gas36, such as compressed CO₂ gas contained in a cartridge 36 and isconnected at another end of the valve 33 and contained within the handle23. Cartridge 36 is a miniature compressed gas cylinder containing acompressed gas such as CO₂ with ability to achieve and deliverypressures as high as 2,000 psi. Valve 33 regulates the release ofcompressed gas from the cartridge 23 into the pressure chamber 27 ofdelivery tube 25 by activation button 74 a located at a convenientlocation on the handle 23, for instance, easily accessible with the padof the fore finger of patient or user's hand.

If desired, a detachably connected cover (not shown) can be used withhandle 23 in order to provide direct access to the gas cartridge 36 forexchanging the cartridge 36 after expenditure of its contents (whenempty) with a freshly charged (full) gas cartridge 36 thereby making thedrug delivery device 20 b a multiple use device or reusable device.

As shown in FIG. 9, nozzle plate 30 and nozzles 34 are located at thedistal end of the delivery tube 25 and pressure chamber 27 and arearranged as outwardly extending protrusions from the outer surface ofnozzle plate 30 for providing the user 90 with tactile feedback for theproper positioning and alignment of the injection nozzles 34 on asurface of the user's body tissue, for instance, on the tissue locatedwithin a nostril of the nose 110 (as shown in FIG. 10) or tissue locatedwithin the patient's mouth (bucal application), such as the gums or roofof the mouth, or a location within a patient's ear, etc. Thus, drugdelivery device 20 b is appropriate for delivering drug 40 to difficultareas to access of a patient's body due to the elongated and low profiledesign.

Drug reservoirs 38, drug 40, reservoir seals 54, pushrods 48, piston 44and O-ring 52 are arranged and function in the same manner or similarfashion as described for the embodiments of FIGS. 1-7B, except thatthese features are located within the delivery tube 25 and pressurechamber 27 at the distal end of the delivery tube 25 and pressurechamber 27.

Pressure chamber 27 allows compressed gas to be released from thecartridge 36 and channels the gas from the handle 23 to the piston 44along the entire length of the delivery tube 25 which provides thedriving force necessary to slidably advance the piston 44 and theaffixed pushrods 48 through the reservoirs 48 causing the pushrods 48 toexpel by microjet propulsion the drug 40 out through the injectionnozzles 34.

Drug delivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20b (FIGS. 8-10) are intended to be compact in design, for example, havingouter surface dimensions measuring about 2.00″ in length and 0.600″ indiameter (for the embodiments of FIGS. 1-4 and FIGS. 5, 6, 7A and 7Brespectively), and very light in weight, for example only weighingseveral ounces. Ergonomically, it may be desirable to increase the sizeor significantly change the geometry, but the underlying functionalityremains exactly the same as that presented in these figures.

Alternatively, the energy source for discharging a driving force to thepiston 44 is compressed gas, such as CO₂ as one example, releasablyhoused in a gas cartridge 36 (FIG. 8). Moreover, the energy source fordischarging a driving force to the piston 44 can be any type of energyforce so long as it is capable of delivering drug under microjetpropulsion according to the requirements set forth below and later inthis disclosure. For example, the energy source must discharge ampleenergy sufficient enough in order to drive main drive piston 44 andassociated pushrods 48 at a driving pressure that ranges from about 800to about 2,000 psi. In turn, the energy and force at the tips ofmicrozzles 34 ranges from about 4,000 to about 25,000 psi at eachmicrozzle tip, and preferably at a range from about 8,000 to about12,000 psi at each microzzle tip, and more preferably at about 10,000psi at each microzzle tip.

The volume of drug 40 delivered under microjet propulsion by drugdelivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b(FIGS. 8-10), in accordance with present invention, is customizable,adjustable and variable in order to accommodate delivery of any type ofdrug, any tissue type, and any type of medical application. Totaldelivered drug volumes may be adjusted according a volume range that isfrom about 10 micro liters (μl) or less to about 1 milliliter (ml) orgreater depending upon the configuration or design of the drug deliverydevice 20, 20 a and 20 b.

Further, the diameter of the injection nozzle(s) 34 are variable andrange from about 10 (μm) to about 50 (μm) or greater, yieldingexceptionally fine injection streams of drug 40 and minimizing thenumber of nerve receptors impacted by an injection thereby reducingtrauma, pain and discomfort for the patient. One aspect of the noveltyand uniqueness of drug delivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6,7A and 7B) and 20 b (FIGS. 8-10) in accordance with the presentinvention is its use of one or more discrete drug reservoirs 38 whichserve as injection chambers wherein each reservoir contains drug 40 as aportion of the overall injection volume of total dosage for drug 40 asbest shown in FIG. 3 (drug delivery device 20 shown in its pre-firedconfiguration prior to delivering drug 40). And, each reservoir 38 hasits own dedicated injection nozzle 34 of extremely small diameter. Forinstance, the diameter of each nozzle 34 ranges from about 10 μm toabout 50 microns μm or from about 0.0004″ to about 0.002″. Thus, drugdelivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b(FIGS. 8-10) in accordance with the present invention divides the totaldelivery volume for drug 40 into and across multiple, discretereservoirs 38 (for those embodiments according to the present inventionhaving more than one injection reservoir 38), and delivers each drugvolume contained therein into the patient's tissue at higher velocitiesas best shown in FIG. 4 (drug delivery device 20 shown in firedconfiguration after delivering drug 40 under microjet propulsion) thanthose injection velocities achieved with the conventional jet injectorssuch as those jet injectors outlined previously.

Accordingly, one advantage associated with drug delivery device 20(FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b (FIGS. 8-10) inaccordance with the present invention is a dramatic decrease in the timerequired to inject drug 40 wherein this time can be as short as 40milliseconds (msec.). Even for a requirement for the delivery of 0.5 cc(or 0.5 ml) injection of drug 40, the injection time achieved by drugdelivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b(FIGS. 8-10) ranges from about 10 msec. to about 200 msec. (and, in oneexample, ranges from about 40 msec. to about 100 msec. for about 0.5 mlof certain types of drugs). A further aspect of the present invention isthat since the area of the jet stream decreases with the square of thediameter, there is nearly a 100-fold reduction in the area of the skinor tissue affected by injection with drug delivery device 20 (FIGS.1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b (FIGS. 8-10) as compared tothe known thinnest conventional hypodermic needle (ultra-fine insulinneedle having a 31-gauge cannula with a diameter of 0.010″).

In one embodiment according to the present invention, drug deliverydevice 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b (FIGS.8-10) is a single-use pre-filled drug delivery device (designed for onetime use as a disposable unit, i.e. one time, single patient use only)that requires no advance preparation or adjustment by the healthcareprovider or the patient. Thus, drug delivery device 20 (FIGS. 1-4), 20 a(FIGS. 5, 6, 7A and 7B) and 20 b (FIGS. 8-10) is ready-to-use asmanufactured and provided.

Alternatively, drug delivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7Aand 7B) and 20 b (FIGS. 8-10) is also intended to be a re-usable unit(for example, the main housing 24, cap 28 with activation button 74 anddelivery tube 25 and handle 23 with activation button 74 a would bere-used and re-sterilized if required) with a single-use, disposableinner assembly that is either pre-filled or reloaded by the patient orhealthcare provider prior to administration, inserted into the housing24 or handle 23 and delivery tube 25 (for the drug delivery device 20 b)and then removed and discarded after use. In this case, the disposableinner assembly comprises primer 68, pyrotechnic charge 64 (or compressedgas cylinder 36), drug reservoir pushrods 48, drug reservoirs 38,injection nozzles 34. The re-usable housing 24 and delivery tube 25 andhandle 23 and other components such as the cap 28 and activation buttons74 and 74 a are made of an appropriate material such as metal or metalalloy capable of withstanding re-use and re-sterilization if needed.

Additionally, in all embodiments of the present invention, the injectionnozzles 34 can be in the form of array of injection nozzles 34 (in anydesired pattern on the nozzle plate 30 and 30 a) that are configuredout-of-plane or at different angles of trajectory, for example, in orderto provide targeted convergence of the drug 40 to either a particulartarget point in tissue, i.e. a single target point in the tissue forreceipt of the entire injected volume of drug 40 or a plurality ofdesired target points in tissue.

Optimization of Microjet Propulsion Drug Delivery and Method ofManufacture

There are two mechanisms that are used to characterize and measure theperformance of the drug delivery device 20 (FIGS. 1-4), 20 a (FIGS. 5,6, 7A and 7B) and 20 b (FIGS. 8-10) according to the present invention.The first mechanism is a predictive model based on the so-calledHagen-Pouiselle equation. This equation was used to estimate the affectsof differing designs in the major elements and components of the drugdelivery device 20 (FIGS. 1-4), 20 a (FIGS. 5, 6, 7A and 7B) and 20 b(FIGS. 8-10) and their methods of use and the resulting driving forcesthat are required to operate the drug delivery device in accordance withthe performance criteria of the present invention. Additionally, theactual forces required to deliver requisite amounts of drug 40 undermicrojet propulsion were determined empirically through both in vitroand in vivo testing. For example, FIG. 11 is a graph representing thefindings of one of these relevant in vitro studies used to determinedepth of penetration versus pressure for the microjet drug deliverydevice (20, 20 a and 20 b) having nozzle diameter of 50 μm and volume ofdrug delivered of 100 μl in accordance with the present invention.

In development and manufacturing of the drug delivery device 20, 20 aand 20 b in accordance with the present invention, there is aforce/volume/length trade-off based on the diameter of the individualdrug reservoirs 38, as well as the diameters of the injection nozzles 34and the desired injection velocity or mass flow rate of the expelleddrug 40 or drug formulation 40. Further, the design of these componentshas implications for the duration of injection, the number of drugreservoirs 38 and injection nozzles 34 that are used, the size of themain piston 44 and even the physical properties needed by the materialsof construction for many of the key elements of the drug delivery device20, 20 a and 20 b.

This relationship is modeled by the Hagen-Pouiselle equation as follows:F=8QμL(R ² /r ⁴)where:

-   -   F=Injection force    -   Q=Flow rate of drug formulation or injectate    -   μ=viscosity of drug formulation or injectate    -   L=Length of injection nozzle    -   R=Radius of drug reservoir    -   r=radius of injection nozzle

To demonstrate the usefulness of this equation, let's assume that it isdesirable to deliver 500 micro liters (½ cc) of an aqueous drugformulation 40 (a drug solution 40 with viscosity μ=1 cps) to thesubcutaneous layer of tissue at a flow rate Q of 5 cc/second. Further,let's assume that we are using an injection microjet or nozzle diameterof 50 microns (0.002″), or r=25 microns (0.001″). While we want tominimize the drug reservoir length, we also want to minimize theinjection force. Thus, while shorter length is better, smaller diameteralso means less force but a longer length. Thus, a convenient size isselected with respect to a reservoir length suitable to a hand-heldmicrojet drug delivery device (20, 20 a and 20 b) while also attemptingto minimize injection force. Consequently, 0.072″ diameter drugreservoirs, or R=0.036″ (0.914 mm) were selected. The length L of theinjection nozzle 34 is determined by manufacturing constraints (a verysmall hole can only be made in a given material for a limited length).Accordingly, it is assumed that a suitable length L is 0.050″ (1.27 mm).Thus, the Hagen-Pouiselle equation can estimate the injection forcerequired for any given injection nozzle as follows:

With:

-   -   Q=5 cc/s    -   μ=1 cps    -   L=0.050″=0.127 cm    -   R=0.036″=0.091 cm    -   r=25 μm=0.0025 cm    -   F=8QμL (R²/r⁴)=10,218,121 dynes or about 23 lbf.

The number of drug reservoirs 38 is determined by the total force themain drive piston 44 can exert divided by the force required to propeleach of the drug reservoir pushrods 48 which act as individual pistonssimultaneously in this example (expressed as a whole integer). Thepractical pressure achieved by either the pyrotechnic charge 64 or acompressed gas cylinder 36 is limited to about 2,000 psi. Consequently,given a main piston 44 diameter of 0.500″ and the resulting area of(0.250″)² times pi=0.196 square inches, the maximum driving forceavailable is 2,000 psi×0.196 square inches or 392 pounds of force. With23 pounds of force required to drive each drug reservoir pushrod 48 and392 pounds of force available, the maximum number of drug reservoirs 38that can be accommodated (as a whole integer) is 392 divided by 23 or atotal of seventeen (17) reservoirs 38.

The length of each drug reservoir 38 is calculated as a result of thevolume requirement for each. For purpose of example, assume that five(5) reservoirs are used. Thus, given that a total of 500 micro liters isrequired to be delivered through the five (5) reservoirs 38, eachreservoir 38 will deliver 100 micro liters of drug 40. Given a reservoirdiameter of 0.072″ (1.83 mm), each reservoir length will be 100 microliters divided by the reservoir area (pi×(0.914 mm)²) or 38.1 mm long(1.50″).

And, the injection flow rate Q has already been defined as 5 cc/s (asoutlined above). Consequently, the total injection time is determined bythe time required to inject the volume of drug 40 contained within eachindividual reservoir 38, which we have found to be 100 micro liters or1/10^(th) of a cc. Thus, the injection time is 0.10 cc times thereciprocal of the flow rate Q or 20 milliseconds.

As a predictive model, the Hagen-Pouiselle equation is a useful tool forpreliminary analysis and prediction of necessary design parameters forthe elements of the drug delivery device 20, 20 a and 20 b, but as wouldbe expected the empirical findings did differ from the predictiveanalysis. Both in vitro testing which included using a 2 mm thickballistics gelatin over a saturated Pluronic (F127) solution and in vivotesting which including testing the drug delivery device in accordancewith the present invention on the hairless guinea pig model haddemonstrated that the drug formulation 40 is required to be pressurizedto approximately 8,000 psi in order to achieve microjet propulsion, i.e.the velocities necessary for the drug formulation 40 to be deliveredthrough the injection nozzles 34 to a depth of penetration in tissue,such as the skin, needed for therapeutic administration, i.e. in thiscase, subcutaneous administration.

Given, for example, that the drug reservoirs 38 have a diameter of0.072″, the cross-sectional area of each drug reservoir 38 is (0.036)²times pi or 0.004 square inches. With force F equal to pressure P timesarea A, the force needed to drive the pushrods 48 to achieve an 8,000psi pressure in the drug formulation 40 is 8,000 times 0.004 orthirty-two (32) pounds of force. This was a modest increase over the 23pounds of force predicted by Hagen-Pouiselle, but certainly along thesame order of magnitude. Much of the increase is explained by thefriction of the sliding reservoir seals 54 and O-ring 52.

Continuing with the values used in the example for the Hagen-Pouiselleequation, assuming that 500 micro liters of drug formulation 40 isrequired for the total administration and five (5) drug reservoirs 38are being used for the design, then each reservoir 38 contains 500/5 or100 micro liters of drug formulation 40. With thirty-two (32) pounds offorce needed for each drug reservoir 38 and the five drug reservoirstotal, it was calculated that 32×5 or 160 pounds of total force isneeded to drive all of the drug reservoir pushrods 48. Thus, the maindrive piston 44 must exert a force of 160 pounds.

Given a diameter of 0.500″ for the main drive piston 44 (note that thisdimension may be higher or lower depending on the application and thepractical ergonomic limitations of physical size), the area of thepiston 44 is (0.250″)² times pi or 0.196″. Thus, the energy source mustapply a pressure of F/A (160/0.196) or 816 psi to the main drive piston44. This pressure requirement is well within the performancespecifications of either a pyrotechnic charge 64 or a miniaturecompressed gas source 36. The lengths of the drug reservoirs 38 andduration of injection will remain the same as those given in theHagen-Pouiselle example.

The main drive piston assembly 44 acts as an accumulator for thepressure generated by the pyrotechnic charge 64 as shown in FIGS. 2, 3,7A and 7B (or, alternatively, a compressed gas source 36 as shown inFIGS. 8 and 10), distributing the pressure and translating it as adriving force to the individual pushrods 48. The pushrods 48 areintegral to the main drive piston 44, so the total load applied to thepiston 44 is transferred proportionally to each of the pushrods 48. Inthe event that a larger size main piston diameter is required, this willtranslate to a larger exerted force for any given engine pressure. Forexample, if the main piston diameter is increased in our previousexamples from 0.500″ to 0.600″, then the resulting force from a maximumengine pressure of 2,000 psi will increase from 2,000 psi×0.196 sq.in.=392 pounds of force to 2,000 psi×0.283 sq. in.=565 pounds of force.This increase in effective driving force permits the use of additionalinjection nozzles 34, which, in turn, reduces the volume in each nozzle34, which, in turn, reduces the duration of the injection time, etc.

Finally, the nozzle geometry is determined by the desired diameter ofthe drug stream, the tensile/yield strength of the materials ofconstruction, and the practical limitations of manufacturing a verysmall orifice at a cost effective economy of scale. While one goal ofachieving a lightweight, compact hand-held drug delivery device 20, 20 aand 20 b with respect to nozzle geometry is “smaller is better”, thereare practical limits to constructing such nozzles 34.

In the known and conventional needle-free drug injectors, these knowndevices have a relatively large orifice (approximately 0.006″-0.008″)because these are the practical limits of high volume injection moldingin suitable thermoplastics (i.e., core pins smaller than this diameterare not practical at the high pressures and high shear required byinjection molding in high volume production).

As noted for the drug delivery device 20, 20 a and 20 b in accordancewith the present invention, the drug delivery device 20, 20 a and 20 buses nozzles 34 in the 10 to 50 micron size and at significantly higheroperating pressure than found with the known, conventional needle freejet injectors, such as those described previously above.

Consequently, drug delivery device 20, 20 a and 20 b in accordance withthe present invention takes advantage of materials having high tensileand burst strength properties for the components of the drug deliverydevice 20, 20 a and 20 b. Such materials include ceramics, variousmetals and metal alloys, high strength engineering thermoplastics (suchas PEEK™, Torlon™, Ultem™, etc.), and others. Thus, the presentinvention is also directed to using the most cost effective combinationof such materials and to minimize part count, i.e. minimize the numberof components and parts required.

Since the material used will need to withstand a given injectionpressure in excess of 8,000 psi immediately at the nozzle tip, it isdesirable to use discrete nozzles 34 fabricated in metal, metal alloy orceramic (for instance, alumina or zirconia) and assemble to the housing24 (FIGS. 1-7B) or delivery tube 25 (FIG. 8) by bonding or ultrasonicwelding, for example. All of these materials can be formed by injectionmolding, although the final nozzle orifice would be secondarily formedusing laser drilling, ultrasonic drilling, wire EDM machining, or thelike. While not currently believed to be practical, developments inmicro-injection molding may make molding of integral, fully finishedinjection nozzles entirely feasible and more cost effective than currentapproaches involving secondary finishing operations. Nonetheless,injection molding in high strength materials coupled with laser drillingto produce precise, repeatable injection nozzles 34 should satisfyengineering and cost requirements associated with the present invention.

In another example in accordance with the present invention, FIGS. 1-4depict various views of the drug delivery device 20 that can be used toaccelerate a multiplicity of small drug volumes 40 to a suitablevelocity for delivery into tissue, for example, across the skin as partof a transdermal drug delivery procedure. Using this example toillustrate the function of the drug delivery device 20 under theassumption that the design of the drug delivery device 20 will require atotal of thirty (30) injection nozzles 34 with each nozzle 34 having adiameter of 40 microns and a calculated drug volume of 3.3 μl per drugreservoir 38, or a total drug volume of 30×3.3=100 μl. Further, given arequired velocity of 200 m/s for delivery of the drug 40, the forceneeded for each injection nozzle 34 can be calculated from theHagen-Poiseuille equation yielding a value of approximately 10 lbs. perinjection nozzle 34. Given thirty (30) injection nozzles 34, the totalrequired loading force is 30×10=300 lbf. Assuming the main piston 44surface area is 1 square inch, then 3.00 psi of pressure is needed toachieve the requisite performance parameters. Again, this performancecriteria is achievable using the miniature compressed gas cylinder 36(FIGS. 8 and 10) or the pyrotechnic charge 64 (FIGS. 2, 3, 7A and 7B).The advantage of the pyrotechnic charge is that the pressure profile canbe controlled throughout the entire dispensing cycle, providing varyingpressures at different times to optimize the drug dispensing. Moreover,as one can readily appreciate, a number of suitable energy sources mayexist that can be used for the purpose of accelerating the drug 40 tothe required velocities in order to achieve microjet propulsion criteriaaccording to the present invention and the examples provided herein arein no way meant to limit the kind of energy source that may be used inthe present invention.

As best illustrated in the graph depicted in FIG. 11, an in vitro studywas conducted for the microjet drug delivery device (20, 20 a and 20 b)in accordance with the present invention in order to determine anoptimal range for the depth of penetration (in cm) versus an optimalrange of pressure (in psi). The nozzle 34 diameter was approximately 50micron diameter wherein the volume of drug 40 delivered wasapproximately 100 μl. As clearly illustrated in FIG. 11, the deliverypressures for the microjet drug delivery device (20, 20 a and 20 b) canreadily be adjusted to target any selected tissues. Thus, the microjetdrug delivery device (20, 20 a and 20 b) is customizable in a mannerthat ensures that any particular drug can be delivered to a particulardepth of penetration in a particular tissue type based on a particulardelivery pressure according to the graph of FIG. 11. Accordingly, thiscustomizable approach even allows for particular layers of tissue to betargeted for drug delivery. For example, the submucousal layer of tissuecan be targeted exactly according to the algorithm depicted in FIG. 11.

Additionally, any number of drug reservoirs 38 and injection nozzles 38can be utilized for the present invention (within practical limits). Asdemonstrated above, this can be anywhere from a single reservoir 38 anda single nozzle 34 to as many as fifty (50) or more reservoirs 38 andnozzles 34 respectively.

Standard semiconductor processes can readily fabricate the injectionnozzles 34 similar to the fabrication of nozzles used in inkjetprinting. Thus, injection nozzles 34 may be mass-produced silicondevices having an orifice diameter of between 3 and 10 microns as oneexample. The injection nozzles 34 can be fabricated as dense arrays on asilicon wafer and subsequently cut to the desired geometry. Waferpatterns, and therefore the array geometry, can be fabricated in anydesired design. Consequently, the micronozzle array can be fabricated inany desired pattern such as a circular, elliptical, or semi-circularpattern, for example, and with any practical density of injectionnozzles 34 that is required. Typically, every effort would be made toreduce the size of injection nozzles 34 and to maximize the number ofinjection nozzles 34 that such a wafer can yield.

Micro-molding of thermoplastics is an emerging technology that may alsobe useful for manufacturing the drug delivery device 20, 20 a and 20 bin accordance with the present invention. The advantages would besignificant. While silicon wafers are planar structures, injectionmolded plastics are not. Thus, the array of injection nozzles 34 can beconfigured out-of-plane, for example, which would provide tremendousbenefit in creating an array that is intended to be positioned with atargeted convergence. A further significant advantage is cost. Amicronozzle array molded in a thermoplastic would cost pennies, incomparison to a silicon device that could easily range into dollars.

Other methods that may be used to construct the micronozzles 34, includemicro-machining the orifices in place as part of the nozzle plate 30 ornozzle plate 30 a having contoured distal end 31 (annular cup),machining or forming the orifices in glass, metal, ceramic, plastic, orother suitable material and then assembling (e.g., press fitting) intothe contoured distal end 31 (annular cup), etc. Like the other majorcomponents of the drug delivery device 20, 20 a and 20 b in accordancewith the present invention, the design or fabrication of themicronozzles 34 is not intended to be limited to a specific embodiment.

Thus, in general, the present invention is directed to a method formaking or manufacturing a drug delivery device 20, 20 a, and 20 b inaccordance with the present invention. Accordingly, this methodcomprises several key steps such as identifying a drug desired to bedelivered (can be based on any desired treatment or diseases state orcondition that is being targeted for treatment). Additionally, a volumeof the drug desired to be delivered is also identified. Moreover, keyparameters for features of the device 20, 20 a and 20 b are determined.This includes parameters such as the diameter for the one or more drugreservoirs 38 and diameter for the one or more injection nozzles 34which are established in advance. Furthermore, a tissue model for thetissue type or disease to be treated is identified. For example, thetissue model is any appropriate in vitro or in vivo model acceptable forthis purpose. Thus, the tissue model can be based on material, forexample, tissue model that is synthetic, natural, mammal (to include anyanimal or human tissue), living tissue, preserved tissue, etc.

Additionally, other key steps include identifying a penetration depth inthe tissue model for the delivery of the drug. This includes targetingany desired or particular layer of the tissue that is consideredappropriate for microjet injection of the drug 40. And, the drug 40 istested in the tissue model by injecting the drug 40 into the tissuemodel using the drug delivery device 20, 20 a and 20 b in accordancewith the present invention under variable pressure until the desiredpenetration depth or desired tissue layer is achieved.

In using the method according to the present invention, an optimalpressure range is identified for the drug delivery device 20, 20 a and20 b that achieves the desired penetration depth or desired tissuelayer. As outlined previously above, an optimal pressure range has beenidentified to be ≦2,000 psi at main piston 44 and an optimal pressurerange of ≦8,000 psi has been identified for the area at a tip of theinjection nozzle 34.

The method according to the present invention also includes usingpredictive modeling for predicting the optimal pressure range requiredby determining the required injection force (F). Determining theinjection force (F) is accomplished according to the formula:F=8QμL(R²/r⁴); where Q=flow rate of drug; μ=viscosity of drug; L=lengthof injection nozzle; R=radius of drug reservoir; and r=radius ofinjection nozzle.

Methods of Use

For transdermal or dermal delivery, the drug delivery device 20 (FIGS.1-4) is in its pre-fired configuration and loaded with the total volumeof drug 40 to be delivered wherein drug delivery device 20 is placedfirmly against and perpendicular to any desired site of injection(typically the back of the arm, the stomach or the thigh) with the skinpinched in a conventional manner. Since the injection nozzles 34terminate as small outward protrusions from the outer surface of nozzleplate 30, the user is provided with instant tactile feedback for theproper positioning and alignment of the injection nozzles 34 on thesurface of the user's body tissue at the desired site of injection.

As best shown in FIG. 4, upon depressing the activation button 74,striker pin 70 strikes primer 68 thereby activating primer 68, which, inturn, cause the extremely rapid combustion of pyrotechnic charge 64.This controlled explosion provides the driving force necessary toslidably advance the piston 44 and the affixed pushrods 48 through thereservoirs 38 causing the pushrods 48 to expel by microjet propulsionthe drug 40 out through the injection nozzles 34.

Although this example described immediately above is directed tosubcutaneous or cutaneous delivery, there are other examples for thedrug delivery device 20 a and 20 b that are used in applications such asintra-ocular (drug delivery device 20 a), intra-oral (drug deliverydevice 20 b), intra-nasal (drug delivery device 20 b), intra-aural (drugdelivery device 20 b), and, more broadly, intra-mucosal delivery ingeneral (drug delivery devices 20, 20 a and 20 b). It should be alsonoted that “transdermal” delivery is intended to mean all forms ofdelivery such as: intradermal, subcutaneous, and intramuscular.

In another embodiment according to the present invention, the drugdelivery device 20 a (FIGS. 5, 6, 7A and 7B) is particularly well suitedfor ocular use and can deliver any drug 40 needed for intra-ocularmicro-injection (especially intra-scleral or intra-vitreal injections).Such drugs known for these particular applications include VEGFantagonists, corticosteroids, and anti-angiogenic drugs in general.Indications treated by the drug delivery device 20 a (FIGS. 5, 6, 7A and7B) in accordance with the present invention include, for example,diabetic retinopathy, macular degeneration and other diseases involvingneovascularization in the eye.

In this embodiment, contoured distal end or cup 31 is placed over or onthe surface of the eye 100 with the open center portion of cup 31overlaying the cornea. The micronozzles or injection nozzles 34 arespaced and configured about the concentric ring of contoured distal end31 such that they are in contact with the sclera. In one embodiment inaccordance with the present invention, the injection nozzles 31 areconfigured in a circular or elliptical pattern. However, it iscontemplated by the present invention that the injection nozzles 34 bearranged or configured in any desired configuration or pattern.

Upon depression of activation button 74, the injection stream of drug40, as shown in FIG. 5, penetrates deep into the eye 100 through thesclera, and into the aqueous humor or the vitreous or any other desiredtissue layer of portion of eye 100. Preferably the injected drug 40under microjet propulsion is targeted toward the back of the eye 100 aspresently depicted. As mentioned previously, currently, many of thedrugs of interest are administered by injecting directly into the eyewith a conventional needle and syringe. As can be greatly appreciated,this is a somewhat risky procedure and requires that the injection beadministered by a trained ophthalmologist. There are significant risksto the patient associated with these conventional techniques and includeretinal detachment, scarring after repeated injections, and evenblindness. Further, the injection itself is dismaying to the patient andrequires that the patient be very still during the several seconds ofthe injection itself.

In the present invention, injection of the drug 40 into the eye 100 isextremely rapid. For example, given a stream velocity of the injecteddrug 40 under microjet propulsion of 100 m/s for a drug reservoir 38having a volume of 20 micro liters, the entire injection only requiresabout 10 milliseconds using drug delivery device 20 a in accordance withthe present invention. Assuming that the patient were to intentionallymove his or her eyes 100 from one side to the other during theinjection, and assuming eye movement occurs at a rate of about 1 cm/s,the eye could only travel about 1/10^(th) of a millimeter in this periodof time, a distance of no consequence when using drug delivery device 20a in accordance with the present invention. Consequently, this inventionalso represents a safer, more comfortable means of administering drugsto the eye 100 for both the physician and patient.

As contemplated by the present invention, drug delivery device 20 a(FIGS. 5, 6, 7A and 7B) in accordance with the present invention offersa number of advantages over the conventional technology and techniques.For instance, the injection nozzles 34 can be designed to “aim” theinjection stream at specific areas in the eye 100 (e.g., the back of theeye 100). Additionally, the depth of penetration of the drug 40 can becontrolled without relying on the skill of the caregiver. Moreover, therisk of injury to the eye 100 is minimized with drug delivery device 20a (FIGS. 5, 6, 7A and 7B) in accordance with the present invention byminimizing the energy and tearing (trauma) to which the eye 100 issubjected due to the extremely rapid nature of the microjet propulsionof the drug into the tissue of the eye 100 (estimated to be as fast asabout 10 milliseconds for injection of small doses of drug 40).

Moreover, the drug delivery device 20 a has the ability to modulate thejet injection energy and injection stream geometry as a means to controlthe depth of delivery of the drug into the eye. Also, the design of themicronozzle geometry allows for the control the stream diameter,trajectory, cohesion, and focus. Additionally, the flexibility in thedesign of the micronozzle array allows for optimization of the drugdelivery profile for any given drug, disease, or site of disease withinthe eye. Furthermore, the drug delivery device 20 a provides anextremely rapid means of administering drug 40 to the eye 100 such thateye movement does not present an element of risk.

Additionally, many drugs 40 currently under pre-clinical and/or clinicalinvestigation are potent drugs and require only periodic administrationof small doses to the eye 100. Drug delivery device 20 a (FIGS. 5, 6, 7Aand 7B) in accordance with the present invention offers a morecontrolled, repeatable, safe, and comfortable means of delivering thesedrugs 40 to the eye 100 over any known devices and techniques availableto date.

Another embodiment in accordance with the present invention is anintra-nasal application depicted in FIG. 10. Accordingly, the drugdelivery device 20 b (FIGS. 8-10) has particularly useful application inadministering CNS (central nervous system) drugs 40 via microjetinjection to the olfactory bulb of the nose 110 of the patient 90.

In this embodiment, drug delivery device 20 b (FIGS. 8-10) is used toprovide direct injection of drug 40 under microjet propulsion into thesubmucousal space of the nose 110 to the CSF of the olfactory lobe. Forthis purpose, doses of drug 40 of 20 mg or greater can be injectedextremely rapidly (<50 milliseconds) into the submucousal space and thedepth of injection can be precisely controlled such that the drug 40 isdelivered precisely to this area without any harm of penetrating to anundesired location.

In another embodiment according to the present invention, drug deliverydevice 20 b is also used for the intra-oral delivery of drug 40 whereinthe drug can be microinjected into any desired area in the mouth such asintra-mucosal for such applications as treating tumors, i.e. targeteddelivery of drug 40 under microjet propulsion aimed at treating a tumor,for example.

In yet another embodiment according to the present invention, drugdelivery device 20 b is used for the intra-aural delivery of drug 40such that drug 40 can be microinjected into any desired portion of theear or auditory canal for treating various diseases and conditions ofthe ear or those conditions that affect hearing, for example.

Additionally, in other embodiments according to the present invention,drug delivery device 20 b is also useful for areas of the body that aredifficult to access such as various canals, passageways, cavities ordifficult surfaces to reach. Extended delivery tube 25 facilitates easyaccess to these injection sites for the injection of drug 40 undermicrojet propulsion to these difficult areas.

Thus, as described above the drug delivery device 20, 20 a and 20 b inaccordance with the present invention has many novel features andadvantages. Some of these novel features and advantages are summarizedhere for convenience such as extremely small injection nozzles (0.002″or smaller); multiple injection reservoirs and injection nozzlesminimizing each volume of injection and injection time resulting in lesspain; customizable, variable pressure injections to include highpressure injection to reach deep tissues and lower pressure to targetmore shallow tissues; ability to concentrate drug dose into a confinedarea or spread it out over a larger surface area; high volume injectionsdivided into a small volume, discrete injectors (can achieve injectionvolumes equivalent to or larger than conventional jet injectors at morerapid delivery times; multiple medical applications (i.e., transdermal,intra-ocular, intranasal, intrabucal, etc.); efficient operation toinclude total energy requirements equivalent to those total energyrequirements available with the prior art devices, but with the presentinvention being much faster in administering the drug and much lesspainful injection for the patient; ability to deliver multiple drugs(i.e., different drugs can be housed in different drug reservoirs whichis something not possible with the known drug delivery devices currentlyavailable); and ability to separate excipients during storage until timeof injection which improves long term stability of the drug 40.

There is no known or existing technology that provides the advantagesafforded by the present invention, including safety, ease of use,precision in both dose and depth of penetration, patient comfort andacceptance. Other advantages associated with the present invention isthat it can provide for the precise, targeted delivery of smallmolecules and large molecules alike to include macromolecules such aslarge proteins, cells or other biological molecules and drugs. And,another advantage is that the microjet drug delivery device inaccordance with the present invention is extremely rapid in its deliveryof the drug, i.e. about ≦10 ms delivery resulting in nearly pain freeinjection.

The present invention contemplates that a significant reduction in thenozzle orifice size will result in reduced pain to the patient. Further,the present invention enables practical new uses of jet injectiontechnology such as transmucosal delivery.

It is an advantage of the present invention that a plurality of nozzlesmay be employed, arranged in an array and having space between eachadjacent nozzle, defining a two-dimensional planar structure that canlie flat on the skin and, thus, ensure perpendicularity.

Moreover, the present invention provides for true needle-free deliveryof drugs regardless of size of the drug molecules involved as well asprovide for true needle-free delivery of drugs with minimal trauma totissue and that are suitable for delivering drugs in sensitive areas ofthe body such as the eye, nasal passageways, mouth, etc.

And, the drug delivery device 20, 20 a and 20 b are simple and efficientin design and construction, low cost and easy to manufacture.Accordingly, the microjet drug delivery device in accordance with thepresent invention has an appropriate design that is extremely suitablefor a single patient use only disposable device if desired.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein, in accordance with the inventive principles disclosed,without departing from the scope of the invention.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes and substitutions will now occur to those skilled inthe art without departing from the invention. Accordingly, it isintended that the invention be limited only by the spirit and scope ofthe appended claims.

1. A device for delivering a drug comprising: a delivery tube, thedelivery tube having a pressure chamber therein; at least one nozzle ata distal end of the delivery tube and in fluid communication with thepressure chamber; a source of drug adjacent the at least one nozzle; ahandle at a proximal end of the delivery tube; and an energy source inthe handle for providing a driving pressure from about 800 to about2,000 psi for driving the drug through the at least one nozzle and outof the delivery tube.
 2. The device according to claim 1, wherein thedrug is driven through the at least one nozzle within a time rangingfrom about 10 msec to about 200 msec upon activation of the energysource.
 3. The device according to claim 2, wherein the at least oneinjection nozzle has a diameter ranging between about 10 μm to about 50μm.
 4. The device according to claim 3, further comprising an activationelement on the handle for activating the energy source.
 5. The deviceaccording to claim 4, further comprising at least one reservoir at thedistal end of the delivery tube for containing the drug within thedelivery tube, the at least one reservoir in fluid communication withthe at least one nozzle.
 6. The device according to claim 5, wherein theat least one reservoir contains a volume of drug ranging from about 10μl to about 1 ml.
 7. The device according to claim 6, further comprisinga piston in the pressure chamber for driving the drug through the atleast one nozzle.
 8. The device according to claim 7, further comprisingat least one pushrod connected to the piston and movably located in theat least one reservoir for driving the drug through the at least onenozzle.
 9. The device according to claim 8, wherein the drug is driventhrough a tip of the at least one nozzle at a pressure ranging fromabout 4,000 to about 25,000 psi.
 10. The device according to claim 9,further comprising a seal in the delivery tube located at a portion ofthe piston.
 11. The device according to claim 10, wherein the sealcomprises as O-ring seal.
 12. The device according to claim 10, furthercomprising a reservoir seal at a distal end of the at least one pushrod.13. The device according to claim 4, further comprising a valve betweenthe energy source and the delivery tube for regulating pressure withinthe pressure chamber of the delivery tube.
 14. The device according toclaim 13, wherein the energy source is compressed gas.
 15. The deviceaccording to claim 14, wherein the compressed gas is contained in acartridge.
 16. The device according to claim 4, further comprising acover detachably connected to the handle for accessing the energysource.
 17. The device according to claim 4, further comprising a nozzleplate at a distal end of the delivery tube and the at least one nozzlearranged within the nozzle plate.
 18. The device according to claim 4,wherein the at least one nozzle extends from the nozzle plate as anoutward projection at the distal tip of the at least one nozzle.
 19. Thedevice according to claim 4, wherein the energy source comprises apyrotechnic charge.
 20. The device according to claim 19, furthercomprising a primer in the handle for igniting the pyrotechnic charge.21. The device according to claim 20, further comprising a striker pinoperatively connected to the activation element for activating theprimer.
 22. The device according to claim 17, wherein the at least onenozzle is arranged to deliver the drug to a target point.
 23. The deviceaccording to claim 22, wherein the at least one nozzle comprises aplurality of nozzles arranged at a distal end of the housing.
 24. Thedevice according to claim 23, wherein the plurality of nozzles arearranged to deliver the drug to a target point.
 25. The device accordingto claim 4, wherein the device is a single patient use only disposabledevice.
 26. The device according to claim 4, wherein the device is are-usable device.
 27. The device according to claim 9, wherein the drugis driven through a tip of the at least one nozzle at a pressure rangingfrom about 8,000 to about 12,000 psi.
 28. The device according to claim27, wherein the drug is driven through a tip of the at least one nozzleat a pressure ranging at about 10,000 psi.